P207 Synergetic effect of amino acid and ketone metabolism underlies empagliflozin-mediated cardioprotection in the type 2 diabetic heart

Abstract

Abstract Funding Acknowledgements Boehringer Ingelheim Background Although emerging evidence has indicated that sodium glucose cotransporter 2 (SGLT2) inhibitors restore impaired cardiac energetics in type 2 diabetes mellitus (T2DM), the underlying molecular mechanisms have yet to be established. Augmented utilization of ketone is one proposed hypothesis, but depletion of succinyl-CoA triggered by the conversion of ketone back to acetyl-CoA by SCOT (succinyl-CoA:3-oxoacid CoA transferase) may hamper oxidative capacity of the tricarboxylic acid (TCA) cycle, which also requires succinyl-CoA. The recent finding that empagliflozin augments systemic amino acid metabolism in patients with T2DM led us to hypothesize that the anaplerotic effect of amino acid on the TCA cycle complements ketone oxidation. Methods and Results Myocardial infarction (MI) was induced in T2DM rats (OLETF) and control rats (LETO). Survival rate at 48 hours after MI was significantly lower in OLETF than in LETO (40% vs 84%), and empagliflozin treatment (10 mg/kg/day, 14 days) before MI improved the survival rate in OLETF to 70%. Metabolome analysis was performed using heart tissues from the non-infarct region 12 hours after MI. Using principal component analysis, data from 92 metabolites that were detected were compressed into 2 dimensions, and the first component (PC1) clearly separated empagliflozin-treated OLETF from non-treated LETO and OLETF. Analysis of factor loading of each metabolite for PC1 revealed that branched chain amino acids leucine, isoleucine and valine, the latter two of which can be oxidized to succynyl-CoA, and β-hydroxybutyrate were the top four metabolites that characterized empagliflozin treatment. Furthermore, in comparison to LETO, OLETF treated with empagliflozin showed 50% higher levels of glutamine and glutamate, both of which can replenish the TCA cycle at the level of α-ketoglutarate. In OLETF, empagliflozin significantly increased the TCA cycle intermediates citrate, cis-aconitate and malate by 74%, 119% and 59%, respectively. OLETF showed 86% higher lactate and 38% lower ATP than those in LETO, but levels of the metabolites were normalized by empagliflozin, suggesting improved glucose oxidation. Conclusions The present analyses showed that amino acid and ketone metabolism are metabolic pathways that are most affected by empagliflozin. Coordination of these "starvation-induced pathways" may underlie the favorable metabolic effect of empagliflozin in T2DM hearts.